Fabry disease (FD) is a rare lysosomal storage disease.1 It is caused by a mutation of the gene for enzyme a-galactosidase A. The decreased enzyme activity causes storage of globotriaosylceramide (Gb3) in lysosomes of various tissues with subsequent damage and eventually organ failure. Cardiac and renal manifestations are the most serious, but involvement of other organs such as central and peripheral nervous tissue, ears, eyes, skin, gastrointestinal tract and lungs is frequent. Clinical manifestation is usually varied. Classical forms with severe mutations includehave multi-organ disease, whereas milder late onset forms may have an involvement of only a single organ (cardiac or renal forms). The milder forms have a preserved residual enzyme activity.
The gene for a-galactosidase A is localised on the X chromosome. However, both males and females suffer from the disease. In only females, however, the manifestation may be of a milder form and the onset is delayed. The explanation may be in random X-inactivation, so-called ‘Lyonisation’, which results in the activity of only one of the two X chromosomes.
The prevalence of the disease is estimated to be 1:40,000 newborn males and 1:20,000 newborn females. Screening studies in Italy, Austria and Taiwan revealed the prevalence of 1:1600–1:4600 newborn males.2–4 Most of them were mutations associated with milder, late onset disease.
The X inheritance pattern means that male patients will have healthy male offspring and all female offspring will carry the mutation. Female patients transfer the mutation to 50% of offspring of both genders.
The classical phenotype manifests in childhood with an involvement of the peripheral nervous system, such as burning pain, paraesthesias, fever, gastrointestinal symptoms and decreased sweating causing low exercise tolerance.5 The prognosis is determined by cardiac and renal involvement. End-stage renal disease presents in the third or fourth decade. Typical corneal opacities do not decrease vision but are important for diagnostic decisions. Hearing loss may be severe and vestibular involvement leads to debilitating vertigo. Angiokeratomas are typical capillary cutaneous or mucosal non-blanching lesions.
The storage of GB3 takes place in all types of cardiac cells (cardiomyocytes, smooth muscle cells, endothelial cells, fibroblasts, etc).
The most frequent cardiac manifestation is left ventricular hypertrophy (Figures 1 and 2). It is usually concentric. In a sample of 30 patients in our centre, it was present in 61% of males and 18% of females.6 Occasionally a dynamic obstruction of the left ventricular outflow tract may be present. Systolic function remains preserved for a long time. Mild valvular heart disease is frequent but in contrast to some other lysosomal storage diseases (for example, mucopolysacharidosis) there is almost no severe valvular involvement. We treated several patients with severe mitral regurgitation partially due to changes in the morphology and function of the left ventricle, partially due to storage in the valve itself. These patients required mitral valve replacement; attempts of valve-sparing surgery were not successful.
Figure 1: The heart of a patient with Fabry disease who died at the age of 54 years because of heart failure. The extreme hypertrophy of left ventricle with a nearly an obliteration of the ventricular cavity. A hypertrophy of the right heart is also apparent. The weight of the heart was 1100g (with permission of Professor Milan Elleder, The Charles University, Prague)
Figure 2: An ultrasound image of the heart (long parasternal axis view). Concentric hypertrophy is evident. RV, right ventricle; IVS, interventricular septum; LV, left ventricle; AO, aorta; LA, left atrium
Conduction abnormalities are frequent. Typically we encounter a short PR interval (Figure 3). In more advanced atrial-ventricular conduction disturbances, a pacemaker implantation may be necessary. Arrhythmias are common. In a sample of 79 British patients, permanent atrial fibrillation occurred in 3.9%, paroxysmal atrial fibrillation occurred in 13.3%, and non-sustained ventricular tachycardia in 8.3% during a two-year follow-up. There was one sudden death, four pacemaker implantations for bradycardia, one biventricular pacemaker and one implantable defibrillator implantation.7
Figure 3: ECG of a female patient with typically short PR interval, voltage criteria of left ventricular hypertrophy, incomplete right bundle branch block and changes in repolarisation
Patients with FD frequently suffer from coronary heart disease. However, the involvement is usually diffuse, making eventual revascularisation difficult.
Transient ischaemic attacks (TIAs) or strokes are also more common and present in a younger age compared with the general population. Classical risk factors of atherosclerosis may be absent (cryptogenic stroke).
The diagnosis is often established with a great delay. It is based on a thorough family history examination, physical, and laboratory examinations. Imaging techniquecs such as echocardiography or magnetic resonance play an important role. The diagnosis is confirmed by an a-galactosidase A activity examination in plasma and leucocytes. The examination has high sensitivity and specificity in male patients, but there is a large overlap with the healthy population in female patients. Molecular genetic testing is important to determine the precise mutation. Mutations can be classified according to the type of gene modification and our knowledge of its effect on disease manifestation can be divided into to several classes (Table 1). Benign mutations are more common and it may not be cost-effective to conduct the molecular genetic testing in all patients, especially in females. The algorithm used in our centre suggests a plausible approach to evaluation and follow-up of patients (Figure 4). There is a screening option with a dried blood spot, but this technique is mainly suitable for males.8 There are some laboratories that use next-generation sequencing from a dried blood spot for the screening of females.13 In the case of prenatal examinations, α-galactosidase A activity and molecular genetic testing may be performed on cells from the amniotic fluid or chorionic villi.14
The treatment may be divided into specific and supportive. Table 2 shows treatment options.
Enzyme-substitution therapy (or enzyme replacement therapy (ERT)) has been available since the beginning of the century.9 After Gaucher disease, FD was the second disease for which a substitution enzyme was developed and successfully used. There are two medications available on the market: agalsidase beta and agalsidase alfa. The first one is produced fromon tissue cultures of ovarian cells from Chinese hamsters and the second one fromof human fibroblasts. They are almost identical; the difference is only in glycosylation and the recommended dose. The enzyme is administered as intravenous infusions every two weeks. It is tolerated well, but rare allergic reactions may be encountered. Several pharmaceutical companies are developing new enzymes for the treatment of FD.
ERT is indicated for males and females with a confirmed diagnosis of FD, who are symptomatic or have evidence of organ involvement (worsening proteinuria with or without renal dysfunction, left ventricular hypertrophy or arrhythmias, neuropathic pain, TIA, stroke, etc.)
ERT showed efficacy and safety in clinical studies. It can clear the Gb3 from tissues and slow progression of the disease. It can stabilise the glomerular filtration rate, slow down or reverse the increase of left ventricular mass and improve the quality of life.10–12 ERT has proven to be more effective if started early, presumably before irreversible changes in organs have occurred.
The increase of enzyme stability may significantly increase its efficacy. Small molecules that bind to the enzyme and release it again in lysosomes can achieve this. The molecules are called pharmacological chaperone. At present there is one medication – migalastat – which has recently been approved. Results of clinical studies are very promising (FACET 011 and ATRACT 012).13,14 The advantage of this treatment is a large distribution volume with a potentially higher bioavailability and that it is administered orally. The problem is that the medication can be effective only in patients with residual enzyme activity in missense mutations.
Gene therapy represents a great hope for patients with FD. Experimental testing on animals with retroviruses as vectors of a healthy gene for a-galactosidase A are currently being carried out. They are based on the fact that even a small increase of enzyme activity (circa 5%) is sufficient to prevent organ damage. The main problem seems to be the immune reaction leading to a damage of the vector.
Proteinuria also has a prognostic importance in patients with FD. As is seen in other nephropathies, angiotensin-converting enzyme (ACE) inhibitors and ‘sartans’ have a benefit even in patients with FD. The proteinuria cannot be controlled by ERT alone but decreases after an addition of the ACE inhibitor or ‘sartan’.15,16
Arrhythmias and conduction abnormalities may require appropriate medications (antiarrhythmics, anticoagulation), cardioversion, pacemaker or ICD implantation. In coronary heart disease, revascularisation may be considered besides medical therapy.
In end-stage renal disease, a standard renal replacement therapy is indicated. The best results can be achieved with renal transplantation.17 The renal graft is not in danger of Gb3 accumulation because it has a proper production of α-galactosidase A.
Treatment of pain presents a problem. In chronic pain, antiepileptics (carbamazepine or phenytoin) and also gabapentin can be administered. In pain crises, non-steroidal anti-inflammatory drugs or opioids can be used. It is important to pinpoint pain triggers such as stress, physical exertion, or changes of temperature.
Prenatal counselling for couples of a fertile age should also be considered.
FD requires a multidisciplinary approach. In different countries we can find physicians of different specialities leading the care of patients with FD. The most important factor is to think about the disease in terms of a multi-organ involvement. The diagnosis can be confirmed easily in males by determining the activity of a-galactosidase A in plasma and leucocytes. The confirmation in females requires molecular genetic testing. Thanks to progress in research into FD and its treatment, intravenous enzyme replacement therapy is available and further experience with the oral pharmacological chaperone, migalastat will soon be available. We will have to wait a little longer for genetic therapy.
1 Desnick RJ et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations
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13 Germain DP et al. Treatment of Fabry’s Disease with the pharmacologic chaperone migalastat. N Engl J Med 2016;375:545–55.
14 Hughes DA et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomized phase III ATTRACT study. J Med Genet 2016;0:1–9.
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17 Ojo A et al. Excellent outcome of renal transplantation in patients with Fabry’s disease. Transplantation 2000;69:2337–9.